Penicillin G is bacteriocidal for sensitive
strains, that is the agent itself can kill the bacteria as
opposed to arrest growth (bacteriostatic)

The principal mechanism for penicillin
bacteriocidal action is inhibition of cell wall synthesis with
penicillin primarily affecting gram-positive organisms.
Furthermore, for both the penicillins and cephalosporins
bacteriocidal activity is dependent on actively growing
bacteria which will be actively synthesizing new cell walls.

Penicillin is relatively nontoxic.

Disadvantages of
Penicillin G

Disadvantages of penicillin G include
the possibility of hypersensitivity reactions, a relatively short
duration of action, and acid lability.

Particularly important concerns with the penicillins is sensitivity
to ß-lactamases (penicillinases) which will limit
effectiveness as well as their general lack of effectiveness
against gram-negative organisms.

Penicillin-binding Proteins (PBPs) catalyze an important step in bacterial
cell wall synthesis [a transpeptidase reaction
which removes a terminal alanine in a
crosslinking reaction with a nearby peptide].

One
mechanism of penicillin antibacterial action is
through binding to these proteins, thereby
inhibiting their activity.

A Mechanism by which bacteria develop resistance
to ß-Lactams
is through alteration
of penicillin-binding proteins (PBPs).

Resistance to beta-lactam antibiotics may be
acquired either by mutation of
existing PBP genes or, more importantly, by
acquiring new PBP genes (e.g. staphlococcal
resistance to methicillin) or by acquiring new
"pieces" of PBP genes (e.g. pneumococcal, gonococcal and meningococcal
resistance).

Most common among
several mechanisms by which bacteria develop
resistance to ß-Lactam
antibiotics is by elaboration of the enzyme ß-lactamase, which hydrolyzes the
ß-lactam ring.

ß-lactamase genes may be found in both gram-positive and
gram-negative bactera.

Clavulanic
acid and sulbactam, by binding to some ß-lactamases, can lessen resistance.

A second
mechanism by which bacteria develop
resistance to ß-Lactams
is through alteration of penicillin-binding
proteins (PBPs):

Either by mutation of
existing PBP genes or, more importantly,
by acquiring new PBP genes (e.g.
staphlococcal resistance to methicillin)
or by acquiring new
"pieces" of PBP genes (e.g. pneumococcal, gonococcal and
meningococcal resistance)

A third
mechanism seen in gram-negative bacteria is
due to alteration of genes that specify outer
membrane proteins (porins) and reduce
permeability to penicillins. (e.g. resistance
of Enterbacteriaceae to some cephalosporins and
that of Pseudomonas spp. to ureidopenicillins)

Multiple resistance
mechanisms may be found in the same bacterial
cell.

All penicillins (excepting semisynthetic, penicillinase-resistant antistaphylococcal agents) can be
hydrolyzed by ß-lactamases enzymes and will not be
efficacious against bacterial strains that produce this
enzyme.

2In the clinical laboratory
setting, E . coli (Escherichia coli) is probably the most commonly
isolated organism. E . coli is a member of the group of
pathogens called coliform bacilli which include these genera
Escherichia, Enterobacter, Citrobacter, Klebsiella, and Serratia.
Additionally, Proteus is a member of this group. Many of these
organisms are normally found in the gastrointestinal tract, thereby
being considered normal flora.

Infections:

Enteric infections -- E . coli is a major
contributor to infections, especially in the developing
countries, as a major enteric (intestinal) pathogen.

Nosocomial infections (hospital acquired
infections) are frequently (frequency = 29% in United
States) due to Coliform and Proteus bacilli. These organisms
are frequently responsible for urinary tract infections
(46%) and infections associated with surgical sites
(24%). E . coli is the most prominent nosocomial
pathogen.

Community-acquired infections:

As noted above for nosocomial infections come E . coli
is prominent as a cause of urinary tract infection's in
the community acquired environment. Urinary tract
infections include prostatitis and pyelonephritis.
Other common pathogens responsible for urinary tract
infection's include Proteus, Klebsiella, and
Enterobacter. Proteus mirabilis is the most likely
cause of infection-related kidney stones.
Klebsiella pneumoniae causes severe pneumonia.

3Moraxella
cattarrhalis, a gram-negative bacteria often found in normal
human upper respiratory tract flora, are similar in appearance to Neisseria cells . Occasionally, Moraxella cattarrhalis may
cause significant lung disease such as pneumonia and acute
bronchitis as well as important systemic infections including
meningitis and endocarditis. In both children and adults, this
organism may be commonly responsible for otitis media, sinusitis,
and conjunctivitis. (Moraxella cattarrhalis may cause as many as 20%
of otitis media presentations)

Moraxella cattarrhalis may be responsible for
lower respiratory tract infection in those adults who have
chronic lung disease.

This organism is often found in the normal
flora and children (frequency = 40%-50%).

Moraxella cattarrhalis can cause symptoms that
are very similar, nearly indistinguishable from those caused by
gonococci, so the differential assessment is quite
important. Also, many Moraxella cattarrhalis strains
elaborate beta-lactamase making them resistance too many beta-lactam
antibiotics.

"Streptococci can survive within pus in a chronic abscess cavity where they are protected from other mechanisms for disposal of bacteria, e.g. macrophages,
opsonising antibodies, complement and, of course, theraputically administered antibiotics.(Gram stain)."
courtesy of-Department of Pathology, University of Birmingham, U.K.

Second generation drugs are active against beta-lactamase producing
H.influenzae. Furthermore, good activity is exhibited against
anaerobes which is a particularly useful characteristic in mixed infections
such as peritonitis.

Third Generation
Cephalosporins are generally more active against gram-negative organisms
(except for the drug cefoperazone (Cefobid)). Some members of this group
have enhanced ability to cross the blood-brain barrier.

Cefuroxime (Zinacef, Ceftin) is
effective in community-acquired pneumonia or take your leave the causative
organism may be beta-lactamase producing H.influenzae or Klebsiella
pneumoniae. Cefuroxime (Zinacef, Ceftin) is the only second-generation
drug across the blood-brain barrier, although third-generation agents such
as ceftriaxone (Rocephin) or cefotaxime (Claforan) or more effective in
managing meningitis.

Cefepime, although classified as a
fourth-generation agent, exhibits many properties of third-generation
cephalosporins. Cefepime (Maxipime) is somewhat more resistant to
hydrolysis by beta-lactamases and exhibits activity against certain beta-lactamases
which inactivate many third-generation drugs.

Cefepime (Maxipime) exhibits activity against
most penicillin-resistant strains of streptococci and has been considered
effective in management of Enterobacter infections. At this agent also
exhibits effectiveness against Staphylococcus aureus, Staphylococcus
pneumoniae, Enterobacteriaceae and P. aeruginosa.

Generally, cefepime (Maxipime) may be
considered clinically comparable to most third-generation cephalosporins.

Synergistic actions with
aminoglycoside antibiotics against some strains
of Pseudomonas aeruginosa. Combination
with an aminoglycoside is recommended because of Pseudomonas rapidly develops resistance to
imipenem.

Agent of
choice for treating Enterobacter infections.

Meropenem has somewhat great
antibacterial effects against gram-negative
aerobes and slightly less activity against
gram-positive organisms.

Meropenem is less seizure producing compared to
imipenem.

Effective in
treating these infections

Urinary
tract

Lower
respiratory tract

Bone

Joint

Skin

Intra-abdominal

Gynecological

Mixed
infections

Endocarditis

Bacterial
septicemia

Contraindications:

Contraindicated: hypersensitive
patients

Safe use in pregnancy (category C)
or in children <12 not established.

Penicillin-binding Proteins (PBPs)
catalyze an important step in bacterial
cell wall synthesis [a transpeptidase
reaction which removes a terminal alanine
in a crosslinking reaction with a nearby
peptide].

One mechanism
of penicillin antibacterial action is
through binding to these proteins,
thereby inhibiting their activity.

Many
factors (age, gender) influence the relationship
between serum creatinine levels and creatinine
clearance. Reliance on estimated creatinine
clearance is appropriate in determining
aminoglycoside dosage in a patient.

In renal
insufficiency, care must be used to avoid
toxicity due to drug accumulation.

Development of
resistance to aminoglycosides

Most common mechanism of
resistance is antibiotic inactivation by
enzyme-mediated covalent modification which
results in phosphate, adenyl or acetyl group
transfer.

Aminoglycoside-modifying enzymes are plasmid
localized.

The modified
antibiotic is also less active because of decreased transport and decreased binding to the
ribosomal target site

Aminoglycoside-modifying enzymes have been found
in both gram-negative and gram-positive bacteria.

Trimethoprim is
an inhibitor of bacterial dihydrofolic acid reductase.

Pyrimethamine
(Daraprim) is an excellent inhibitor of
dihydrofolic acid reductase in protozoa

These reductases are required for
the synthesis of purines and hence DNA.

Inhibition
of these enzymes are responsible for
bacteriostatic and bacteriocidal activities.

When
trimethoprim or pyrimethamine is combined with sulfonamides (sulfamethoxazole)
there is sequential blocking of the biosynthetic
pathway leading to drug synergism and enhanced
antimicrobial activity. (see figure below)

Resistance to trimethoprim:
usually by plasmid encoded trimethoprim-resistant
dihydrofolate reductases.

Trimethoprim typically used orally
often in combination with sulfamethoxazole, a
sulfonamide with a similar half-life.

By I.V.
administration trimethoprim - sulfamethoxazole: agent
of choice for moderately severe to severe
infections with
Pneumocystis carinii
pneumonia, especially in patients with
HIV. May be used for
gram-negative sepsis

DNA gyrase inhibitors: The function of DNA gyrases, and the
effects of their inhibition; clinical uses of
quinolones and fluoroquinolones; adverse effects and
potential drug-drug interaction for quinolones.